Breaking the antimicrobial resistance dilemma: marine natural products, a treasure trove for the development of new anti-Staphylococcus aureus drugs

Abstract

Antimicrobial resistance (AMR) affects multiple fields, including medicine, pharmacy, food safety, and animal husbandry, and poses a major threat to public health and economic development. Staphylococcus aureus has emerged as one of the most critical bacterial pathogens due to its widespread prevalence and significant genetic plasticity. This review outlines currently approved small-molecule drugs for clinical use and their mechanisms in controlling bacterial infections and antimicrobial resistance, highlighting the development of novel agents as an effective strategy to combat AMR. Special emphasis is placed on the antibacterial activity of marine-derived natural products (MNPs) against S. aureus , and a systematic analysis is presented for the first time on the structures, origins, activities, and structure–activity relationships of 1,192 compounds reported in 468 publications from 1977 to 2025. Among these, 36 MNPs exhibited significant activity against both methicillin-sensitive S. aureus and methicillin-resistant S. aureus (MIC ≤ 1 µg/mL). Macrolides and peptides represented the most prevalent structural classes, with compounds displaying potent activity accounting for 24% and 27% of the total active compounds, respectively. Further drug-likeness analysis shows that MNPs have promising therapeutic potential. Among the 160 highly active MNPs, over 80% have suitable lipid-water partition coefficients, and 41% fully meet Lipinski's Rule of Five. Structural analysis reveals tetrahydrofuran, tetrahydropyran, and sugar units as the most common motifs, present in 20, 16, and 14 compounds, respectively. Technologies and strategies to accelerate the development of marine-derived antibacterial drugs are also proposed. This will serve stakeholders across diverse sectors by supporting cross-sectoral coordination to address AMR.

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